Introduction

Patients with inflammatory bowel diseases (IBD) frequently experience fatigue, affecting up to 80% of those with active disease and approximately 50% with quiescent disease (1). The exact cause of IBD-associated fatigue is often unknown, making clinical management very challenging. Previous studies have suggested the potential involvement of infectious triggers and host immune responses in the development of fatigue.

Aims & Methods

In this study, we aimed to explore whether patients with quiescent IBD reporting fatigue exhibit specific systemic antibody responses, which could provide insight into potential immune reactivities underlying fatigue.
Systemic antibody epitope repertoires were profiled leveraging PhIP-Seq against 344,000 rationally selected peptide antigens. Fatigue severity was assessed on a 10-point Likert scale, ranging from 1 (no fatigue) to 10 (highest fatigue severity). Quiescent IBD was defined as clinical (Harvey-Bradshaw Index [HBI] <5 or Simple Clinical Colitis Activity Index [SCCAI] <2.5) and biochemical remission (C-reactive protein [CRP] <5 mg/L) at time of sampling. Multivariable logistic regression analyses, allowing adjustment for potential confounding factors e.g. age, sex, and smoking, were performed to identify associations between fatigue and systemic antibody responses.

Results

In total, 327 patients with IBD (156 with Crohn’s disease [CD]; 171 ulcerative colitis [UC]) were profiled. A total of 153 different antibody-bound peptides were identified in association with fatigue considering nominal significance (nominal P-value <0.05), in the absence of significant associations after adjustment for multiple comparisons. Among antibodies nominally significantly associated with fatigue, 56 antibody-bound peptides (36.6%) were found in lower frequency among highly fatigued patients (fourth quartile, Q4), while 97 peptides (63.4%) were identified as more frequent in highly fatigued patients compared to those with lower fatigue scores (<Q4). Among highly fatigued patients, elevated antibody responses were primarily directed towards viral antigens, with by far the strongest signal against several antigens from Epstein-Barr virus (EBV), mostly directed at the EBV nuclear antigens 1 (EBNA-1) and 3B (EBNA-3B). In addition, elevated antibody responses were observed against bacterial antigens, including functional proteins from Streptococcus and Staphylococcus species. Most findings remained materially unchanged when we repeated analyses solely in patients with quiescent IBD, although antibody responses against EBV were altered, e.g. showing lower responses directed against the BLRF/BMRF/EA-D pathway. Furthermore, these antibody signatures were distinct from those recently identified in association with chronic fatigue syndrome (CFS) (2).

Conclusion

Fatigue in IBD is not reflected by distinct antibody epitope repertoires. However, our study suggests a potential involvement of viral antigens, particularly EBV, in IBD-associated fatigue. Although larger confirmatory studies are needed to validate these findings, this study shows that a technology like PhIP-Seq may represent a valuable strategy to approach the investigation of immune responses underlying complex symptoms such as fatigue.

References

1. D’Silva A, Fox DE, Nasser Y, Vallance JK, Quinn RR, Ronksley PE, et al. Prevalence and Risk Factors for Fatigue in Adults With Inflammatory Bowel Disease: A Systematic Review With Meta-Analysis. Clinical Gastroenterology and Hepatology. 2022;20(5):995-1009.e7. doi:10.1016/j.cgh.2021.06.034

2. Vogl T, Kalka IN, Klompus S, Leviatan S, Weinberger A, Segal E. Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients. Sci Adv. 2022;8(38). doi:10.1126/sciadv.abq2422